Worldwide tuberculosis is the leading cause of death attributable to a single infectious agent. In most cases, it is a chronic pulmonary disease necessitating prolonged therapy. An antigen-specific T cell- mediated host response is critical for the containment of infection with M. Tuberculosis. Several cytokines, including IFN-gamma and TNF-alpha, have been implicated as critical in the systemic T cell mediated host response to this organism. Studies addressing the specific pulmonary host response to M. Tuberculosis are limited, even though the lung is the portal of entry for this pathogen. To investigate the role of specific cytokines in pulmonary host response to M. Tuberculosis, this study will use a transgenic mouse (SPCTNFRIIFc) in which a soluble inhibitor of TNF-alpha is expressed in the lung and produces a lung specific blockade of TNF-alpha. This transgenic mouse has been shown in preliminary studies to express the transgene exclusively in the lung, and to secrete a functional soluble inhibitor of TNF-alpha. An additional transgenic mouse model (SPCIFNRFc) will be designed and generated, in which a soluble inhibitor of IFN-gamma is expressed in the lung and produces a localized pulmonary blockade of the effects of IFN-gamma. The IFNRFC transgenic mouse will be fully characterized and then utilized in subsequent mycobacterial experiments. Transgenic mice (SPCTNFRIIFc AND SPCIFNRFc), wildtype mice and mice with disrupted genes for IFN-gamma (GKO) and the type I TNF-alpha receptor (TNFRI-/-) will be infected with virulent M. Tuberculosis by both the aerosol and intravenous routes. Combining both routes of infection will aid in demonstrating the specific effects of pulmonary blockade of either TNF-alpha or IFN-gamma. Mycobacterial burden in various tissues and survival will be determined to gauge the effectiveness of the emerging host response. Tissue histology, cytokine production and the emergence of specific lymphocyte cell populations locally and systemically will be measured to characterize the nature of the specific pulmonary host response to M. Tuberculosis infection. This study should add to the understanding of the specific nature of the pulmonary immune response to M. Tuberculosis, may also contribute to the development of immunomodulatory therapies to treat refractory tuberculosis and ultimately may lead to the development of more effective vaccines. This project will allow me to build on the foundation of knowledge obtained during my pediatric infectious disease fellowship regarding the investigation of host response. I plan continued contribution to the academic community through patient care of children with infectious diseases and through research into the specific nature of the host-pathogen interaction.